The present invention relates to a process for making duloxetine and its related compounds as well as to intermediates useful therein.
Duloxetine is a pharmaceutically active compound useful as an antidepressant. Chemically duloxetine is S(+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine of the formula (1a),
and is commonly used in pharmaceutical compositions as its hydrochloride salt. The marketed pharmaceutical dosage form of duloxetine, sold under such brand names as CYMBALTA®, is a capsule comprising a plurality of enteric coated pellets containing duloxetine hydrochloride. It is believed that the pharmaceutical formulation of the actually marketed pellets is covered by EP 693282 (U.S. Pat. No. 5,508,276) of Eli Lilly & Co.
EP 273,658 describes a variety of 3-aryloxy-3-substituted propanamines including duloxetine and the racemate thereof. The general reaction scheme can be represented as follows:

By Mannich reaction of 2-acetylthiophene 2 with paraformaldehyde and dimethylamine hydrochloride, the starting dimethylaminoketone 3 is obtained. The ketone 3 is reduced to the hydroxyl compound 4. The reduction can be stereo-specific, it can be racemic, or the racemate or mixture can be resolved. Thus, mixtures of the optical isomer as well as the pure or relatively pure optical isomer are contemplated by the above formula 4 and 5. After coupling with the fluoronaphthylene group, the compound is subjected to demethylation to form 1 or 1a if stereospecific intermediates were used. Alternatively, the racemate 1 can be resolved such as by a resolving agent, chromatography, etc., to form 1a, i.e., duloxetine. The synthesis was discussed in more detail in Deeter, et al., in Tetrahedron Letters, 31(49), 7101-04 (1990) and elaborations, variants, modifications and/or improvements have been taught or suggested in U.S. Pat. No. 5,362,886 (EP 650965), EP4575599 WO 00-061540, WO 03-97632 (EP 1506965), WO2004-056795 and WO 2006-045225.
The above general scheme, however, requires a demethylation step. This can be unattractive as the demethylation step usually employs toxic and irritating haloformates. Additionally, the condensation of the compound 4 with 1-fluoronaphthalene is often accompanied with a loss of chirality, though this can be minimized according to U.S. Pat. No. 5,362,886 by the use/presence of potassium compounds.
WO 2004/005307 describes forming duloxetine by the use of a methylamine as follows:
The resolving of the racemate 7 into the isomer 7a is specifically described. The compound 6 can be made by an analogous Mannich reaction as in the case of making the compound 3. Several other patents describe making or using such a compound (see WO 2004-031168, WO 2004-005307, WO 2004-005239, WO 2004-065376). But the preparation of 6 by Mannich reaction can be problematic as high levels of impurities can arise such as of the dimeric products (tertiary keto-amines). This is likely a result of the fact that the aminic nitrogen contains a hydrogen that is susceptible to side reactions. Moreover, the compound 6 is a relatively unstable compound, particularly in the form of free base. Therefore, reduction procedures leading to 7 and employing alkaline conditions run with a low yield and, when an attempt for the enantio-selective reduction is made, with a low selectivity.
WO 03-070720 describes another variant wherein a compound 3.1 is first converted to a keto-carbamate 8 and then reduced to the corresponding alcohol 9. The reduction can be stereospecific and/or the enantiomers can be resolved. The carbamate is subsequently hydrolysed to form 7 and then converted to duloxetine. In making duloxetine, the reaction can be represented as follows:
The preferred group R is a benzyl group. The Compound 2 is apparently an intermediate in the above-mentioned demethylation of 4 to 7. The process can thus suffer from the similar disadvantages as in other processes that use a demethylation step.
Additional processes for making duloxetine are disclosed in WO 2004-013123, US 2003-0225153, WO 2004-024708, in Chirality 2000, 12, 26-29, in Drugs of the Future 2000, 25(9), 907-916, and in Adv. Synth. Catal. 2003, 354, 261-274, WO 03-97632, WO 2004-005307, WO 03-062219, WO 03-070720, and JP 2004/123596.
Albeit many synthetic attempts were made, there is still a need for a convenient simple process for making duloxetine.